The “Indian Superbug”: Worse Than We Knew

Just about a month ago, the disease-geek world was riveted by news of the “Indian superbug“: common bacteria carrying a newly recognized gene that confers profound multi-drug resistance, and that was linked to travel between Europe and South Asia, especially for medical tourism.

The gene, which directs production of an enzyme called NDM-1 for short, was briefly Bug of the Week, the spur for alarmist headlines in every Internet echo chamber and the target of denunciations by Indian politicians, who vilified the discovery as a Western “pharma conspiracy” spurred by envy of lucrative medical tourism.

And then, just as quickly as it popped into public consciousness, NDM-1 slid back under the news-radar horizon.

Or so it seemed. Researchers though remain deeply concerned about NDM-1, along with a wider array of dire resistance factors of which it has suddenly become the best-known. This week, I’m at ICAAC (the annual Interscience Conference on Antimicrobial Agents and Chemotherapy), an enormous 12,000-person meeting focused on infectious diseases and the drugs to treat them, and talk of NDM-1 is everywhere.

The news is not good. This new resistance factor has been found so far in the United States, Canada, Belgium, the Netherlands, Austria, France, Germany, Oman, Kenya, Australia, Hong Kong and Japan. Most of the isolates, the bacterial samples in which it has been identified, are susceptible to only one or two remaining antibiotics. One was susceptible to none.

“These resistant bugs,” Dr. Patrice Nordmann, a professor of clinical microbiology at the South-Paris Medical School, said in a briefing here, “have already spread all over the world.”

A brief recap:

NDM-1 was first spotted in 2008, in a 59-year-old man of South Asian origin who lived in Sweden. He was hospitalized on a visit home to New Delhi, had surgery, recovered, went back to Sweden and was hospitalized there again. At that point, physicians recognized that he had a urinary tract infection that was unusually drug-resistant. The infection was caused by a common bacterium, Klebsiella pneumoniae, but the Klebsiella possessed an unusual and worrisome ability to disable carbapenems, a class of drugs given for very resistant infections. They named the enzyme and the gene directing its production for the place where the man had apparently acquired it: New Delhi metallo-beta-lactamase, and blaNDM.

In 2009, the United Kingdom’s public-health agency sent out an alert saying the same resistance mechanism was appearing there and increasing rapidly, going from unknown in 2007 to 18 instances in the first half of 2009, most of them in people who had gone to India for medical care or had frequent family travel back and forth. In June this year, the US Centers for Disease Control and Prevention put out a bulletin about NDM-1’s first US appearance, in three patients in three different states (California, Massachusetts and Illinois), again with ties to South Asian medical care.

And then, confirming this really was something to be concerned about, last month the journal Lancet Infectious Diseases published the results of a survey for NDM-1 that the authors conducted with collaborators in India, Pakistan and the UK. They found it widely distributed in Klebsiella and E. coli in South Asia; in UK residents who had family or business ties to South Asia or had gone there for care; and also in people who had never left the UK. Shortly afterward, the World Health Organization warned governments that they should be taking this new arrival seriously.

In the few papers on NDM-1 that got rustled up in time for ICAAC, there are more details on NDM-1’s behavior in patients in Australia, Canada, Kenya and the US; the patients were infected with different organisms, but the organisms all possessed the same gene, and were all susceptible at best to one or two drugs, some new, some old and with toxic side-effects. What connects that handful of reports: much more detail on the mobile genetic elements where the NDM gene resides. It is on more than one plasmid; it can move freely between plasmids; the plasmids have been shown to move not just between individual bacteria, but also between species and genera. Overall, that adds up to a resistance mechanism that is spreading with remarkable speed — and bringing with it, as fellow-travelers on the same plasmids, even more resistance mechanisms that have not yet been delineated.

(I can’t link to the work presented at ICAAC because it is not online, but the teams are: Nordmann and colleagues from the Hospital Bicetre in Paris; Timothy Walsh and team from University of Cardiff, who made the first identification in 2008; Brandi Limbago and colleagues from the CDC; and JDD Pitout et al. from the University of Calgary.)

But if you know a new resistance mechanism is spreading worldwide, what do you do about it? That’s the larger discussion percolating through the corridors here. Antibiotic resistance has always been a biological occurrence wrapped in layers of science, economics and politics. For NDM-1, the politics are especially difficult.

In South Asia, several of the researchers pointed out, antibiotic overuse is common, diarrheal disease is endemic, and municipal sanitation is available to only about half of the more than 1 billion population. That’s practically a recipe for the rapid spread of genetic material carried by gut bacteria — and the economic realities of the subcontinent make it unlikely that any of those conditions are going to be remedied soon. At the same time, the South Asian diaspora worldwide is millions of people, and no one wants to be in the position of blaming a country or a people for antibiotic Armageddon.

There’s a clear concern that everyday physicians may see cases of this and not know what they are seeing. These infections look like any other — or will, until the point when patients don’t get better. At that point, what appeared to be a simple urinary tract infection, for instance, can climb backward to the kidneys, enter the bloodstream, and turn deadly. “General practitioners are not used to seeing multi-drug resistant bacteria in the community,” Dr. Pitout said. “If this does become common, it will lead to a lot of failure of treatment.”

When H1N1 swine flu became a worldwide concern last year, and H5N1 flu five years before that, the World Health Organization mobilized an intricate network of influenza surveillance labs around the world to detect aberrant isolates and track their movement. Amazingly, there’s no such network for antibiotic resistance, Nordmann said. And though an international network for the detection of antibiotic resistance would have been useful before — to track the movement of MRSA, for instance — the researchers agreed it is critically needed now. But that’s not an easy demand to satisfy. The flu network is substantially supported by the governments of the countries where the labs are located (the US lab in the WHO network is within the flu division of the CDC). Governments may not have the money available, and may not agree this issue is as high a priority as the West believes.

This week, France will begin screening any new hospital patients, checking to see who has been treated in a South Asian hospital and so may be a source of NDM-1. That’s a first step, and a crucial one. “The only practical advice I can give at this moment is for physicians to ask their patients,” Pitout said. “And if you have been treated abroad and you develop a medical emergency and must be treated at home, it is very important to tell your physician.”